Aspirating Implants and Method of Bony Regeneration

ABSTRACT

Devices and methods for in situ drawing, filtering and seeding cells from the marrow of surrounding bone into a fusion cage without any of the challenges mentioned above. Various implants and devices with aspiration ports that enable in-situ harvesting and mixing of stem cells. These devices may include spinal fusion cages, long bone spacers, lateral grafts and joint replacement devices. Each device utilizes at least one aspiration port for harvesting of stem cell-containing marrow via aspiration from adjacent bony elements.

CONTINUING DATA

This patent application is a continuation of and claims priority fromcopending U.S. Ser. No. 12/634,647, filed Dec. 9, 2009, entitled“Aspirating Implants and Method of Bony Regeneration” (O'Neil), thespecification of which is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Because bone regeneration is generally required to obtain successfuloutcomes for many common orthopedic procedures, osteoregenerativeproducts such as allograft, bone substitutes, morphogenic proteins andosteoregenerative mixes are widely used by clinicians. In theseprocedures, both compression-resistant and non-compression resistantbone substitutes are frequently mixed with allograft as well asautologous materials including marrow and bone.

Current procedures for harvesting autologous stem cells from bone marrowhave incorporated methods to enhance stem cell filtering, mixing orseeding to improve viability of implant matrixes. For example, U.S. Pat.No. 5,824,084 (Muschler) discloses a method of preparing a compositebone graft. Unfortunately, some disadvantages are associated with theseprocedures. For example, the time and exposure required during themixing of bone, bone substitutes matrix's with autologous bone oraspirate can significantly delay the surgical procedures, increasing therisk of infection and blood loss.

Also, the bone marrow aspiration procedure often requires an addedsurgery for harvesting of BMA or bone from adjacent vertebrae,processes, ribs or the iliac crest. Spinal surgical fusion proceduresrequire the endplates to burred and roughened to allow marrow to bleedinto the interbody graft. This added time and effort increases operatingroom demand, anesthesia requirements, infectious disease exposure, andblood loss, all of which impact patient outcomes as well as procedurecost. Lastly, conventional prefilled graft materials are not designed tomaximize stem cell retention.

Thus, there is a need for a procedure and devices for harvesting stemcells that reduces collateral damage, infection risk, operating roomtime, operating room effort for graft mixing and packing, and provides agraft that enhances stem cell attachment.

US Published Patent Application No. 2008154377 (Voellmicke) discloses anintervertebral fusion cage that is adapted to contain an inserter withinits inner volume during insertion of the cage.

Curylo, Spine, 24(5), 1 Mar. 1999, pp 434-438 discloses augmentation ofspinal arthrodesis with autologous bone marrow in a rabbitposterolateral spine fusion model.

Bo{hacek over (z)}idar {hacek over (S)}ebeèiæ, Croatian Medical Journal,March 1999 (Volume 40, Number 3) discloses percutaneous autologous bonemarrow grafting on the site of tibial delayed union.

Becker, Spine, 31 (1), 2006, pp. 11-17, discloses osteopromotion by aβ-tricalcium phosphate/bone marrow hybrid implant for use in spinesurgery.

SUMMARY OF THE INVENTION

This invention provides devices and methods for the in-situ drawing,filtering and seeding of cells from the marrow of surrounding bone intoan implanted fusion cage.

In particular, the present invention includes various implants withaspiration ports and other devices that enable in-situ harvesting andmixing of stem cells. These devices may include spinal fusion cages,long bone spacers, lateral grafts and joint replacement devices. Eachimplant utilizes at least one aspiration port for the in situ harvestingof stem cell-containing marrow via aspiration from adjacent decorticatedbony elements.

In some embodiments, some of the following components that enable stemcell collection are employed:

-   -   fusion device aspiration ports,    -   fusion device covers or sheaths that improve the suction through        the cage;    -   porous sheets that allow suction therethrough but retain cells,    -   graft matrixes designed for controlled stem cell filtering,        collection and bony regeneration, and    -   insertion and aspiration instruments including a flexible        aspiration funnel.

These components allow for effective retention of stem cells but withoutthe time-consuming and invasive ex vivo harvesting, ex vivo mixing andex vivo handling of conventionally—obtained graft.

Therefore, in accordance with the present invention, there is providedan intervertebral fusion assembly, comprising:

-   -   a) an intervertebral fusion cage, comprising:        -   i) an upper surface adapted for gripping an upper vertebral            body and comprising an upper throughole therethrough,        -   ii) a lower surface adapted for gripping a lower vertebral            body and comprising a lower throughole therethrough,        -   iii) a sidewall connecting the upper and lower surfaces and            comprising an aspiration port therethrough, and    -   b) an aspirator,        wherein the aspirator connects to the aspiration port to provide        fluid connection between the fusion cage and the aspirator.

DESCRIPTION OF THE FIGURES

FIGS. 1 a-d discloses side and front views of intervertebral fusioncages of the present invention.

FIG. 2 a discloses a side view of an assembly of the present invention,with the cage thereof implanted in a disc space.

FIG. 2 b discloses use of the assembly.

FIG. 3 a discloses an exploded assembly of the present invention.

FIG. 3 b discloses a side view of another exploded assembly of thepresent invention, with the cage thereof implanted in a disc space.

FIG. 3 c discloses a perspective view of an aspiration cage of thepresent invention.

FIG. 3 d discloses a side view of an aspiration cage of the presentinvention wrapped in a graft containment bag (or sheath).

FIGS. 4 a-4 b disclose a tube-like load bearing device of the presentinvention implanted in a long bone.

FIGS. 5 a-f disclose a method of the present invention being carried outin a long bone defect.

FIG. 6 discloses a method of the present invention being carried out onan iliac crest.

FIGS. 7 a-7 f disclose steps for implanting a long bone plug of thepresent invention in a contained bony defect.

FIG. 8 discloses an aspirating graft jacket implanted between adjacenttransverse processes.

FIG. 9 discloses an aspirating graft jacket having nanotubes.

FIGS. 10 a-d disclose cages of the present invention with various ports.

FIGS. 10 e-f disclose side and front views of a duckbill-type enclosedvalve.

FIG. 11 discloses an aspirating cage of the present invention having anendplate seal.

FIG. 12 discloses an aspirating cage of the present invention in whichthe endplate seal has teeth extending therefrom.

FIG. 13 shows an aspirating cage of the present invention filled with aporous matrix.

FIGS. 14 a-c show an aspirating cage of the present invention having twoports.

FIG. 15 discloses the cage of the present invention attached to aninsertion device.

DETAILED DESCRIPTION OF THE INVENTION

Several aspirating devices and methods are disclosed that improve stemcell filtering, enhance mixing, increase bony regeneration, and reducethe risk of infection. These devices and methods include both implantsand instruments that facilitate the in-situ aspiration and mixing ofnative autograft. The use of such devices and methods subsequentlyresult in bone regeneration without the added operative procedure,manual variability and infection risk associated with the conventionalharvesting and external mixing of stem cells.

In some embodiments, the aspiration port may be selected from the groupconsisting of a simple hole, a threaded hole, a pierceable membrane suchas a septum, a cannulated projection extending out of the implant, and arecess extending into the implant. In some embodiments, the implantincludes more than one such aspiration port.

The port (or aspiration line) may incorporate a one-way valve to enableaspiration while preventing subsequent leakage. The port (or aspirationline) may also have a bi-directional valve that enables both a) theaspiration of aspirate into the implant (by drawing a vacuum through theport), and b) the injection of biologics (such as cells, BMPs, drugs,anesthetics, analgesics, or antibiotics) directly into the porous matrixof the implant to enhance bone growth (by injecting through the port).

The ports may further include modular attachment means forintra-operative insertion, aspiration and/or injection.

The port may be designed to have a control feature that controls processvariables such as flow rate, pressure and/or delivery of the aspiratethrough the porous bone substitute matrixes.

The implants may be in the form of a bag, tube or cage. They may bepre-operatively or intra-operatively filled with bone-inducing porousmatrixes.

In the case of spinal fusion cages, openings in the bone-contactingsurfaces (or endplates) of the cage enable marrow aspirationtherethrough following aggravation of the natural endplates to initiatevascular/marrow flow. Such a cage having teeth on its endplates can bemanipulated in-situ to decorticate the bone and thereby enhance vascularflow and aspirate filtering. The spinal-fusion cage can have limitedlateral/posterior holes to control vacuum pressure and maximize vascularflow. The endplates of the cage may include peripheral sealing as ameans to enhance flow, fit, or conformation or provide for added vacuumcapabilities with adjacent endplates. The cage can be fabricated with orplaced within a bag (made of, for example, collagen or resorbablepolymer) to contain vascularity and stem cells during and afteraspiration.

Now referring to FIGS. 1 a-d, there are provided front and side views ofintervertebral fusion cages of the present invention. FIGS. 1 a-bdisclose a standard mesh-type cage 1 fitted with an aspiration port 3.The cage has been filled with a porous matrix 5 (in this case, a bonyregeneration matrix) to assist in the retention of the stem cells in thecage. In some embodiments, the upper 7 and lower 9 surfaces of the cagehave been beveled to increase endplate vascularity. FIGS. 1 c-d disclosefront and side views of the cages of FIGS. 1 a-b, but with a sheath 13wrapped around the cylindrical portion of the cage. These sheaths helpedretain the suction produced by the aspiration.

Now referring to FIG. 2 a, there is disclosed a side view of an assemblyof the present invention, with the cage 15 thereof implanted in a discspace. In use, the plunger 17 of the aspiration syringe 19 is slowlywithdrawn, thereby reducing the pressure in the air-tight cage. The lowpressure in the cage causes bone marrow to move from the adjacentvertebral bodies into the cage (as shown by the plurality of arrows).The porous matrix provided in the cage retains the stems cells presentin the marrow.

In some embodiments, the marrow collected in the syringe is re-injectedthrough the cage in order to retain even more stem cells on the porousmatrix.

FIG. 2 b discloses use of the assembly.

Now referring to FIGS. 3 a-d, there are provided various aspirator cagesof the present invention. FIG. 3 a discloses an exploded assembly of thepresent invention in which the port 21 of the cage 23 is aligned withthe needle 25 of an aspirating syringe 27. In FIG. 3 b, there is a sideview of another exploded assembly of the present invention, with thecage 23 thereof implanted in a disc space. The distal end 29 of anaspiration line 31 is connected to the port 21 of the cage 23, while theproximal end 33 of the line is fitted with a valve 35. The purpose ofthe valve is to allow for disconnection without leakage. Duringaspiration, the valve will hold the negative pressure. Duringdispensing, the valve insures the dispensing pressure and preventsleakage. The valve can also control excess vacuum pressure for apredetermined time.

The valve is also adapted for connection to the distal end 37 of theneedle of an aspirating syringe 27. FIG. 3 c discloses a perspectiveview of an aspiration cage 39 of the present invention. This cage has aport 21 to which an aspiration line 31 is connected. The cage is alsofilled with porous matrix 41 for retaining the stem cells thereon. FIG.3 d discloses a side view of an aspiration cage 43 of the presentinvention wrapped in a graft containment bag 45 (or sheath).

The aspirating and filtering devices of the present invention can alsobe used to create long bone graft spacers with enhanced viability andreduced surgical risk. These tubular spacers may be fabricated frompolymers, ceramics, or bone substitutes. They can be preoperatively orintra-operatively filled with porous bone substitute matrixes.Aspiration port(s) on the long bone spacer enable marrow aspiration andstem cell filtering to enhance viability of the device.

Therefore, and now referring to FIGS. 4 a-b, there is provided a methodof treating a long bone defect 51 having opposing cancellous surfaces53, comprising the step of:

-   -   a) inserting a fusion cage 55 into the defect, the cage having        an aspiration port 57 and opposing porous endplates 59,    -   b) orienting the cage so that each porous endplate of the cage        abuts one of the cancellous surfaces,    -   c) fluidly connecting an aspirator 61 to the port, and    -   d) actuating the aspirator to lower pressure in the cage,        thereby drawing bone marrow from the cancellous surfaces into        the cage.

In one preferred embodiment, an implant of the present invention is usedto improve the healing of a contained defect. In use, the defect isfirst is filled with bone substitutes or matrixes and covered with anosteoconductive porous sheet or matrix. In-situ bone marrow (containingstem cells) is then aspirated though the porous sheet and the stem cellsare seeded onto the matrix and sheet. This procedure may be accomplishedwith or without an aspiration port via a flexible and conforming funnelaspirator. The funnel can be deployed minimally invasively to bothdeliver and implant the porous sheet onto the defect.

Now referring to FIG. 5 a, the procedure begins with creating anapproach to the bony defect BD. Now referring to FIG. 5 b, the defect BDis debrided. Now referring to FIG. 5 c, the debrided area is filled witha porous matrix 63 (for example, a bone substitute or an expandablegel). Now referring to FIG. 5 d, a porous cover sheet 65 is applied overthe porous matrix housed in the debrided area. The cover sheet is thenattached with either fasteners or an adhesive (neither shown). Nowreferring to FIG. 5 e, a flexible aspiration funnel 67 is then laid uponthe porous cover sheet. Now referring to FIG. 5 f, an aspirator 69 isfluidly connected to the funnel, and a vacuum is drawn through the coversheet to aspirate marrow into the porous matrix. The vacuum pressureassociated with the aspiration is monitored and cut off when a desiredpressure is obtained, or when the cover sheet or matrix becomes occludedwith marrow.

Therefore, in accordance with the present invention, there is provided amethod of treating a contained bony defect, comprising the steps of:

-   -   a) debriding the bony defect,    -   b) filling the defect with a porous matrix,    -   c) placing a porous sheet over the porous matrix,    -   d) placing a flexible funnel on the porous sheet, the funnel        being fluidly connected to an aspirator, and    -   e) actuating the aspirator to draw bone marrow from the defect        into the porous matrix and cover sheet.

Now referring to FIG. 6, this flexible aspiration method described inFIGS. 5 a-5 f can also be utilized for other bony defects, including theiliac crest. Now referring to FIG. 6, there is provided a method of thepresent invention being carried out on an iliac crest, wherein theflexible funnel 67 and aspirator 69 draw bone marrow out of the pelvicregion and into the porous matrix contained within the iliac crest sothat the stem cells in the marrow are retained on the porous matrix.

Now referring to FIGS. 7 a-f, contained defects can be filled withaspirating bone plugs 71 that include ports or covers to facilitatemarrow aspiration and stem cell filtering. FIG. 7 a discloses such apreferred device of the present invention.

Now referring to FIG. 7 a, the procedure begins with creating anapproach to the bony defect BD. Now referring to FIG. 7 b, the defect BDis debrided. Now referring to FIG. 7 c, the debrided area is filled witha fusion device 71 consisting essentially of inorganic bone or bonesubstitute. FIG. 7 d shows a side view of the fusion device of FIG. 7 c.This allograft device is cylindrical in structure and made from aportion of a human femoral, tibial or ulnar long bone. On one end of thedevice, there is an aspiration port 73 adapted for connection to anaspirator. On the peripheral surface 75 of the device, there are aplurality of securement features 77 (such as teeth). In someembodiments, the device is fabricated from bone substitute and made sothat its pores facilitate growth in the longitudinal/axial direction.Now referring to FIG. 7 e, an aspirator (such as a syringe 79) isfluidly connected to the port of the fusion device. Lastly, and nowreferring to FIG. 7 f, aspiration is applied to draw marrow out of theadjacent bone and into the porous bone plug, wherein the stem cells areretained.

Therefore, in accordance with the present invention, there is provided amethod of treating a contained bony defect, comprising the steps of:

-   -   a) debriding the bony defect,    -   b) filling the defect with a porous allograft plug,    -   c) fluidly connecting the plug to an aspirator, and    -   d) actuating the aspirator to draw bone marrow from the defect        into the porous allograft plug.

In some embodiments, the bone substitutes can be in the form ofprefabricated semi-porous bags that are placed within bony structures toenable aspiration of stem cell from adjacent bony structures. The “graftjacket” may be utilized for lateral graft in spinal procedures. Thisdevice is placed in a generally axial direction to provide intimatecontact against opposing transverse processes, which can beintraoperatively burred to enhance vascularity.

Now referring to FIG. 8, there is provided an aspirating graft jacket ofthe present invention. The graft jacket 81 comprising:

-   -   a) an expandable bag 83 having upper and lower throughholes 85        and an aspiration port 87, and    -   b) a porous matrix (not shown) contained within the bag.

In use, the surgeon first aggravates the opposing faces of adjacenttransverse processes in order to induce blood flow. Next, the surgeonplaces the aspirating graft jacket between the transverse processes,with the throughholes contacting the aggravated faces of the transverseprocesses. Next, the surgeon places an aspirator in fluid connectionwith the aspiration port of the graft jacket. Lastly, the surgeonapplies a vacuum to the aspirator to draw marrow from the transverseprocesses and into the graft jacket.

Therefore, in accordance with the present invention, there is provided amethod of fusing a spine between adjacent transverse processes,comprising the steps of:

-   -   a) decorticating opposing faces of the adjacent transverse        processes,    -   b) placing a graft jacket having an aspiration port between the        opposing faces so that upper and lower throughholes of the graft        jacket contact the opposing faces,    -   c) fluidly connecting the port to an aspirator, and    -   d) actuating the aspirator to draw bone marrow from the        transverse processes into the cage.

Now referring to FIG. 9, in some embodiments, the graft jacket of thepresent invention may contain nanotubes 99 extending longitudinallybetween the opposing open endfaces of the cage having ports 100. Theaxial nature of the nanotubes augments the load-bearing abilities of thegraft jacket and further aids the capillary wicking of vascular flow tofurther enhance directional bone formation. Nanotubes can be producedfrom either carbon, metallics (titanium), polymers (such as PEEK, CFRP,or PET), or ceramics. Nanotubes can be produced from bone substitutesincluding CaP, HA, or TCP.

Now referring to FIGS. 10 a-f, there are provided other embodiments ofan intervertebral cage having a port. The port may be in the form of anopening 101 (as in FIG. 10 a), a septum 103 (as in FIG. 10 b), anenclosed valve 105 (as in FIG. 10 d), or an in-line valve 107 (as inFIG. 10 c). When an enclosed valve is selected, it is preferably in theform of a duckbill-type valve, as shown in FIGS. 10 e and 10 f. The portmay be advantageously used for a) in-situ aspiration of autologousmaterial (such as adjacent blood, marrow and stem cells); b) dispensingof bioreactive materials (such as graft, INJECTOS, bone marrow aspirate,and growth factors such as BMPs); and c) re-dispensing of materials postoperatively (such as in the event of a failed fusion).

Now referring to FIG. 11, there is provided another embodiment of thepresent invention describing a cage 109 with a port 110 and acompressible endplate seal 11. The compressible endplate seal typicallylines an opening in the top or bottom of the cage and is made ofelastomers (such as urethane, TPE, thermoplastic polymers andsilicones), hydrogels, flexible resorbable polymers, or collagen. Thecompressible endplate seal provides a number of advantageous functions,including enhancing endplate contact, enhancing vacuum of adjacentmarrow, containing aspirate, and containing dispensate.

Therefore, in accordance with the present invention, there is providedan intervertebral fusion cage, comprising:

-   -   a) an upper surface adapted for gripping an upper vertebral body        and comprising an upper throughole therethrough,    -   b) a lower surface adapted for gripping a lower vertebral body        and comprising a lower throughole therethrough,    -   c) a sidewall connecting the upper and lower surfaces and        comprising an aspiration port therethrough, and        at least one compressible endplate seal disposed about either        the upper or lower throughhole.

Now referring to FIG. 12, there is provided another embodiment of thepresent invention, describing a cage with a port, an endplate seal and aplurality of teeth 113 extending from the seal. The teeth may be usedfor gripping the opposing endplates and to initiate bleeding bone andmarrow flow.

In some embodiments, the teeth that extend from the cage of the presentinvention are cannulated. These cannulated teeth can be deployed intothe endplates once the cage is placed into the interbody space. In someembodiments, the inserter has a feature that triggers the spikes todeploy after insertion. Thus once the syringe is attached it would drawin marrow from the endplates through the holes in these cannulatedteeth.

Now referring to FIG. 13, there is provided another embodiment of thepresent invention describing a cage with a port, an endplate seal withteeth, and a prefilled graft 115 within the cage. The graft acts as afilter to desirably increase stem cell selection/retention. In someembodiments, the graft has a pore size of between about 10 and about 20μm and is treated with one or more of the following.

-   -   a. Type 1 or 2 collagen,    -   b. fibrinogen, fibronectin, and/or thrombin, or    -   c. gelatin.        In some embodiments, a sheath (not shown) may be disposed around        the cage of FIG. 13. The sheath may be used to advantageously        enhance vacuum of adjacent marrow, contain aspirate, and contain        dispensate.

Now referring to FIG. 14, there is provided another embodiment of thepresent invention describing a cage having two ports 121, 123. The pairof ports can be used to provide for dual aspiration. One of the portscan be a dedicated dispensing port for dispensing materials such as bonemarrow aspirate, PRP, growth factors such as BMP. The dual ports can beused with a baffle 125 to set up circulation in the cage (with one portallowing inflow and the other allowing only outflow, as in FIG. 14 c).In one such circulation embodiment, the circulation provides forenhanced filtering. In another embodiment, recirculation is provided.

Now referring to FIG. 15, in some embodiments, the cage 130 may beinserted into the disc space with an inserter 132 substantially similarto that disclosed in U.S. Pat. Nos. 6,478,800 and 6,755,841 (thespecifications of which are hereby incorporated by reference in theirentireties), but with a syringe 131 and needle 133 replacing the medialshaft that connects with the implant.

In some embodiments, sufficient bone marrow is drawn into the cage tosubstantially fill the cage with bone marrow. However, it is known thatstem cells selectively adhere to the surfaces of many porous media.Therefore, in other embodiments, an excess of bone marrow is drawn fromthe vertebral bodies and through the cage in order to concentrate thestem cells in the porous media of the cage.

The porous media is made from a biocompatible, implantable graftmaterial. Preferably, the material has a charged surface. Examples ofbiocompatible, implantable graft materials having a charged surfaceinclude synthetic ceramics comprising calcium phosphate, some polymers,demineralized bone matrix, or mineralized bone matrix.

More preferably, cell adhesion molecules are bound to the surface of theporous media. The term “cell adhesion molecules” includes but is notlimited to laminins, fibronectin, vitronectin, vascular cell adhesionmolecules (V-CAM), intercellular adhesion molecules (I-CAM) andcollagen.

In some embodiments, the cell adhesion molecule preferentially bindsstem cells. In other embodiments, the cell adhesion molecule has a lowaffinity for partially or fully differentiated blood cells.

In some embodiments, the cage of the present invention includes a drugdelivery reservoir. These reservoirs serve the same function as drugdelivery microspheres but provide a more structured approach.

It is believed that a consistent and controlled flow rate of marrowthrough the cage will create the environment best suited for cellattachment. Preferably, the cage is designed (and the flow rate isselected) so that the flow of marrow therethrough fills the porousmatrix in a reasonable time period, but does not flow so fast that shearstresses cause the stem cells to lyse.

The load-bearing fusion device of the present invention may beconstructed of metals (such as Ti, Ti64, CoCr, and stainless steel),polymers (such as PEEK, polyethylene, polypropylene, and PET),resorbable polymers (such as PLA, PDA, PEO, PEG, PVA, andcapralactides), and allograft, bone substitutes (such as TCP, HA, andCaP)

The fusion device housing of the present invention can be made of anystructural biocompatible material including resorbable (PLA, PLGA,etc.), non-resorbable polymers (CFRP, PEEK, UHMWPE, PDS), metallics (SS,Ti-6Al-4V, CoCr, etc.), as well as materials that are designed toencourage bony regeneration (allograft, bone substitute-loaded polymers,growth factor-loaded polymers, ceramics, etc.). The materials for thefusion device housing are biocompatible and generally similar to thosedisclosed in the prior art. Examples of such materials are metal, PEEKand ceramic.

In preferred embodiments, the fusion device housing is manufactured froma material that possesses the desirable strength and stiffnesscharacteristics for use as a fusion cage component. These components ofthe present invention may be made from any non-resorbable materialappropriate for human surgical implantation, including but not limitedto, surgically appropriate metals, and non-metallic materials, such ascarbon fiber composites, polymers and ceramics.

In some embodiments, the cage material is selected from the groupconsisting of PEEK, ceramic and metallic. The cage material ispreferably selected from the group consisting of metal and composite(such as PEEK/carbon fiber).

If a metal is chosen as the material of construction for a component,then the metal is preferably selected from the group consisting oftitanium, titanium alloys (such as Ti-6Al-4V), chrome alloys (such asCrCo or Cr—Co—Mo) and stainless steel.

If a polymer is chosen as a material of construction for a component,then the polymer is preferably selected from the group consisting ofpolyesters, (particularly aromatic esters such as polyalkyleneterephthalates, polyamides; polyalkenes; poly(vinyl fluoride); PTFE;polyarylethyl ketone PAEK; polyphenylene and mixtures thereof.

If a ceramic is chosen as the material of construction for a component,then the ceramic is preferably selected from the group consisting ofalumina, zirconia and mixtures thereof. It is preferred to select analumina-zirconia ceramic, such as BIOLOX delta™, available from CeramTecof Plochingen, Germany.

In some embodiments, the cage member comprises PEEK. In others, it is aceramic.

In some embodiments, the fusion device housing consists essentially of ametallic material, preferably a titanium alloy or a chrome-cobalt alloy.

In some embodiments, the fusion device housing components are made of astainless steel alloy, preferably BioDur^(R) CCM Plus^(R) Alloyavailable from Carpenter Specialty Alloys, Carpenter TechnologyCorporation of Wyomissing, Pa. In some embodiments, the fusion devicehousing components are coated with a sintered beadcoating, preferablyPorocoat™, available from DePuy Orthopaedics of Warsaw, Ind.

In some embodiments, the fusion device housing is made from a compositecomprising carbon fiber. Composites comprising carbon fiber areadvantageous in that they typically have a strength and stiffness thatis superior to neat polymer materials such as a polyarylethyl ketonePAEK. In some embodiments, the fusion device housing is made from apolymer composite such as a PEKK-carbon fiber composite.

Preferably, the composite comprising carbon fiber further comprises apolymer. Preferably, the polymer is a polyarylethyl ketone (PAEK). Morepreferably, the PAEK is selected from the group consisting ofpolyetherether ketone (PEEK), polyether ketone ketone (PEKK) andpolyether ketone (PEK). In preferred embodiments, the PAEK is PEEK.

In some embodiments, the carbon fiber comprises between 1 vol % and 60vol % (more preferably, between 10 vol % and 50 vol %) of the composite.In some embodiments, the polymer and carbon fibers are homogeneouslymixed. In others, the material is a laminate. In some embodiments, thecarbon fiber is present in a chopped state. Preferably, the choppedcarbon fibers have a median length of between 1 mm and 12 mm, morepreferably between 4.5 mm and 7.5 mm. In some embodiments, the carbonfiber is present as continuous strands.

In especially preferred embodiments, the composite comprises:

-   -   a) 40-99% (more preferably, 60-80 vol %) polyarylethyl ketone        (PAEK), and    -   b) 1-60% (more preferably, 20-40 vol %) carbon fiber,        wherein the polyarylethyl ketone (PAEK) is selected from the        group consisting of polyetherether ketone (PEEK), polyether        ketone ketone (PEKK) and polyether ketone (PEK).

In some embodiments, the composite consists essentially of PAEK andcarbon fiber. More preferably, the composite comprises 60-80 wt % PAEKand 20-40 wt % carbon fiber. Still more preferably the compositecomprises 65-75 wt % PAEK and 25-35 wt % carbon fiber.

In general, the housing is typically filled with at least one boneforming agent (BFA). The bone-forming agent may be:

-   -   a) a growth factor (such as an osteoinductive or angiogenic        factor),    -   b) osteoconductive (such as a porous matrix of granules),    -   c) osteogenic (such as viable osteoprogenitor cells), or    -   d) plasmid DNA.

In some embodiments, the housing contains a liquid carrier, and the boneforming agent is soluble in the carrier.

In some embodiments, the bone forming agent is a growth factor. As usedherein, the term “growth factor” encompasses any cellular product thatmodulates the growth or differentiation of other cells, particularlyconnective tissue progenitor cells. The growth factors that may be usedin accordance with the present invention include, but are not limitedto, members of the fibroblast growth factor family, including acidic andbasic fibroblast growth factor (FGF-1 and FGF-2) and FGF-4; members ofthe platelet-derived growth factor (PDGF) family, including PDGF-AB,PDGF-BB and PDGF-AA; EGFs; VEGF; members of the insulin-like growthfactor (IGF) family, including IGF-I and -II; the TGF-β superfamily,including TGF-β1, 2 and 3; osteoid-inducing factor (OIF), angiogenin(s);endothelins; hepatocyte growth factor and keratinocyte growth factor;members of the bone morphogenetic proteins (BMPs) BMP-3, BMP-2, OP-1,BMP-2A, BMP-2B, BMP-7 and BMP-14, including HBGF-1 and HBGF-2; growthdifferentiation factors (GDFs), members of the hedgehog family ofproteins, including indian, sonic and desert hedgehog; ADMP-1;bone-forming members of the interleukin (IL) family; rhGDF-5; andmembers of the colony-stimulating factor (CSF) family, including CSF-1,G-CSF, and GM-CSF; and isoforms thereof.

In some embodiments, platelet concentrate is provided as the boneforming agent. In one embodiment, the growth factors released by theplatelets are present in an amount at least two-fold (e.g., four-fold)greater than the amount found in the blood from which the platelets weretaken. In some embodiments, the platelet concentrate is autologous. Insome embodiments, the platelet concentrate is platelet rich plasma(PRP). PRP is advantageous because it contains growth factors that canrestimulate the growth of the bone, and because its fibrin matrixprovides a suitable scaffold for new tissue growth.

In some embodiments, the bone forming agent comprises an effectiveamount of a bone morphogenic protein (BMP). BMPs beneficially increasingbone formation by promoting the differentiation of mesenchymal stemcells (MSCs) into osteoblasts and their proliferation.

In some embodiments, between about 1 ng and about 10 mg of BMP areadministered into the target disc space. In some embodiments, betweenabout 1 microgram (μg) and about 1 mg of BMP are administered into thetarget disc space.

In many preferred embodiments, the bone forming agent is a porousmatrix, and is preferably injectable.

The porous matrix of the present invention may contain porous orsemi-porous collagen, extracellular matrices, metals (such as Ti, Ti64,CoCr, and stainless steel), polymers (such as PEEK, polyethylene,polypropylene, and PET) resorbable polymers (such as PLA, PDA, PEO, PEG,PVA, and capralactides), bone substitutes (such as TCP, HA, and CaP),autograft, allograft, xenograft, and/or blends thereof. Matrices may beorientated to enable flow from bony attachment locations to theaspiration port. Matrices may be layered with varying densities, porestructures, materials to enable increase stem filter at desiredlocations via density, pore size, affinity, as well as fluid flowcontrol (laminar, turbilant, and/or tortuous path).

In some embodiments, the porous matrix is a mineral. In one embodiment,this mineral comprises calcium and phosphorus. In some embodiments, themineral is selected from the group consisting of calcium phosphate,tricalcium phosphate and hydroxyapatite. In one embodiment, the averageporosity of the matrix is between about 20 and about 500 μm, forexample, between about 50 and about 250 μm. In yet other embodiments ofthe present invention, in situ porosity is produced in the injectedmatrix to produce a porous scaffold in the interbody space. Once the insitu porosity is produced in the space, the surgeon can inject othertherapeutic compounds into the porosity, thereby treating thesurrounding tissues and enhancing the remodeling process of the targettissue.

In some embodiments, the mineral is administered in a granule form. Itis believed that the administration of granular minerals promotes theformation of the bone growth around the minerals such thatosteointegration occurs.

In some embodiments, the mineral is administered in a settable-pasteform. In this condition, the paste sets up in vivo, and therebyimmediately imparts post-treatment mechanical support to the interbodyspace.

In another embodiment, the treatment is delivered via injectableabsorbable or non-absorbable cement to the target space. The treatmentis formulated using bioabsorbable macro-sphere technologies, such thatit will allow the release of the bone forming agent. The cement willprovide the initial stability required to treat pain in target tissues.These tissues include, but are not limited to, hips, knee, vertebralbody and iliac crest. In some embodiments, the cement is selected fromthe group consisting of calcium phosphate, tricalcium phosphate andhydroxyapatite. In other embodiments, the cement is any hardbiocompatible cement, including PMMA, processed autogenous and allograftbone. Hydroxylapatite is a preferred cement because of its strength andbiological profile. Tricalcium phosphate may also be used alone or incombination with hydroxylapatite, particularly if some degree ofresorption is desired in the cement.

In some embodiments, the porous matrix comprises a resorbable polymericmaterial.

In some embodiments, the bone forming agent comprises an injectableprecursor fluid that produces the in situ formation of a mineralizedcollagen composite. In some embodiments, the injectable precursor fluidcomprises:

-   -   a) a first formulation comprising an acid-soluble type I        collagen solution (preferably between about 1 mg/ml and about 7        mg/ml collagen) and    -   b) a second formulation comprising liposomes containing calcium        and phosphate.

Combining the acid-soluble collagen solution with the calcium- andphosphate-loaded liposomes results in a liposome/collagen precursorfluid, which, when heated from room temperature to 37° C., forms amineralized collagen gel.

In some embodiments, the liposomes are loaded withdipalmitoylphosphatidylcholine (90 mol %) and dimyristoylphosphatidylcholine (10 mol %). These liposomes are stable at roomtemperature but form calcium phosphate mineral when heated above 35° C.,a consequence of the release of entrapped salts at the lipid chainmelting transition. One such technology is disclosed in Pederson,Biomaterials 24: 4881-4890 (2003), the specification of which isincorporated herein by reference in its entirety.

Alternatively, the in situ mineralization of collagen could be achievedby an increase in temperature achieved by other types of reactionsincluding, but not limited to, chemical, enzymatic, magnetic, electric,photo- or nuclear. Suitable sources thereof include light, chemicalreaction, enzymatically controlled reaction and an electric wireembedded in the material. To further elucidate the electric wireapproach, a wire can first be embedded in the space, heated to createthe calcium deposition, and then withdrawn. In some embodiments, thiswire may be a shape memory such as nitinol that can form the shape.Alternatively, an electrically-conducting polymer can be selected as thetemperature raising element. This polymer is heated to form thecollagen, and is then subject to disintegration and resorption in situ,thereby providing space adjacent the mineralized collagen for the boneto form.

In some embodiments, the osteoconductive material comprises calcium andphosphorus. In some embodiments, the osteoconductive material compriseshydroxyapatite. In some embodiments, the osteoconductive materialcomprises collagen. In some embodiments, the osteoconductive material isin a particulate form.

Specific matrices may be incorporated into the device to provide loadbearing qualities, enable directional bone formation, and/or controldensity of regenerated bone (cortical vs cancellous) or enable cellformation for soft tissue attachment. Nanotubes or nanocrystals can beorientated in a generally axial direction to provide for load bearingabilities as well as capillary wicking of vascular flow to furtherenhance directional bone formation. Biocompatible nanotubes cancurrently be produced from either carbon or titanium or bone substitutesincluding Ca, HA, and TCP.

In one embodiment, the bone forming agent is a plurality of viable exvivo osteoprogenitor cells. Such viable cells, introduced into theinterbody space, have the capability of at least partially supplementingthe in situ drawn stem cells in the generation of new bone for theinterbody space.

In some embodiments, these cells are obtained from another humanindividual (allograft), while in other embodiments, the cells areobtained from the same individual (autograft). In some embodiments, thecells are taken from bone tissue, while in others, the cells are takenfrom a non-bone tissue (and may, for example, be mesenchymal stem cells,chondrocytes or fibroblasts). In others, autograft osteocytes (such asfrom the knee, hip, shoulder, finger or ear) may be used.

In one embodiment, when viable ex vivo cells are selected as anadditional therapeutic agent or substance, the viable cells comprisemesenchymal stem cells (MSCs). MSCs provide a special advantage foradministration into the interbody space because it is believed that theycan more readily survive the relatively harsh environment present in thespace; that they have a desirable level of plasticity; and that theyhave the ability to proliferate and differentiate into the desiredcells.

In some embodiments, the mesenchymal stem cells are obtained from bonemarrow, such as autologous bone marrow. In others, the mesenchymal stemcells are obtained from adipose tissue, preferably autologous adiposetissue.

In some embodiments, the mesenchymal stem cells injected into theinterbody space are provided in an unconcentrated form, e.g., from freshbone marrow. In others, they are provided in a concentrated form. Whenprovided in concentrated form, they can be uncultured. Uncultured,concentrated MSCs can be readily obtained by centrifugation, filtration,or immuno-absorption. When filtration is selected, the methods disclosedin U.S. Pat. No. 6,049,026 (“Muschler”), the specification of which isincorporated herein by reference in its entirety, can be used. In someembodiments, the matrix used to filter and concentrate the MSCs is alsoadministered into the interbody space.

In some embodiments, bone cells (which may be from either an allogeneicor an autologous source) or mesenchymal stem cells, may be geneticallymodified to produce an osteoinductive bone anabolic agent which could bechosen from the list of growth factors named herein. The production ofthese osteopromotive agents may lead to bone growth.

Recent work has shown that plasmid DNA will not elicit an inflammatoryresponse as does the use of viral vectors. Genes encoding bone(anabolic) agents such as BMP may be efficacious if injected into theuncoupled resorbing bone. In addition, overexpression of any of thegrowth factors provided herein or other agents which would limit localosteoclast activity would have positive effects on bone growth. In oneembodiment, the plasmid contains the genetic code for human TGF-β orerythropoietin (EPO).

Accordingly, in some embodiments, the additional therapeutic agent isselected from the group consisting of viable cells and plasmid DNA.

A matrix may be made from hydrogels or may incorporate a hydrogel ascomponent of the final stucture. A hydrogel may be used to expand andenhance filling, improve handling characteristics or increase vacuumpressure. The increased vacuum pressure may be used to determineadequate hydration/stem cell filtration.

In all cases, excess bone marrow aspirate can be collected and mixedwith added graft extenders including collagen like the HEALOS™,INJECTOS™ and HEALOS FX™, each of which is available from DePuy SpineInc, Raynham, Mass., USA.

Although the present invention has been described with reference to itspreferred embodiments, those skillful in the art will recognize changesthat may be made in form and structure which do not depart from thespirit of the invention.

We claim:
 1. A method of treating a bone defect with a fusion cagecomprising: i) a proximal surface comprising a first througholetherethrough, ii) a distal surface comprising a second througholetherethrough, iii) a peripheral sidewall connecting the proximal anddistal surfaces and comprising at least a third throughhole, comprisingthe steps of: a) inserting the fusion cage into the bone defect wherebythe proximal surface faces away from the bone defect, b) covering thefirst throughhole with a cell-impermeable porous sheath, c) attaching anaspirator to the cell-impermeable porous sheath, and d) actuating theaspirator to apply suction through the sheath and draw bone marrowthrough the sidewall and into the cage.
 2. A method of charging a fusioncage having an aspiration port with bone marrow aspirate, comprising thesteps of: a) inserting the fusion cage into an interbody space definedby opposing bones, b) fluidly connecting the aspirator to the aspirationport, and c) creating suction in the aspirator to draw bone marrow fromat least one of the bones into the fusion device.
 3. The method of claim2 wherein the opposing bones have opposing endplates that have beenrasped.
 4. The method of claim 2 wherein the aspiration port and theaspirator have mating lock fittings.
 5. The method of claim 2 whereinthe aspirator is a syringe.
 6. The method of claim 2 wherein a sidewallof the cage has at least one throughhole.
 7. The method of claim 6wherein the cage further comprises a fluid-tight jacket wrapped aroundthe sidewall to occlude the throughhole.
 8. The method of claim 2wherein bone marrow substantially fills the fusion cage.
 9. The methodof claim 2 wherein an excess of bone marrow is drawn through the cage toconcentrate stem cells in the cage.